Development of Novel Cholecystokinin 2 Receptor-Targeted Radioligand Containing Albumin Binder for Efficient...

Theranostics, an integrated approach combining cancer diagnosis and therapy, has gained increasing attention, particularly in the field of radiotheranostics using radioligands. The cholecystokinin 2 receptor (CCK2R), which is overexpressed in various neuroendocrine tumors (NETs), is considered a promising target for radiotheranostic applications. However, the currently available CCK2R-targeted ligand, DOTA-MGS5, exhibits limited tumor accumulation. Incorporation of an albumin binder (ALB) unit, which is capable of interacting with serum albumin, has been reported to enhance tumor accumulation of radioligands by prolonging their biological half-lives. To establish a more efficient CCK2R-targeted radiotheranostic strategy, we developed a novel CCK2R-targeted ALB-containing radioligand, [¹¹¹In]In/[¹⁷⁷Lu]Lu-MGS5-DA, based on DOTA-MGS5. In biodistribution studies, [¹¹¹In]In-MGS5-DA showed markedly higher tumor accumulation compared with [¹¹¹In]In-DOTA-MGS5. Moreover, single-photon emission computed tomography/computed tomography (SPECT/CT) imaging confirmed that [¹¹¹In]In-MGS5-DA could be used to clearly visualize CCK2R-expressing tumors. In a peptide receptor radionuclide therapy (PRRT) study, [¹⁷⁷Lu]Lu-MGS5-DA led to greater tumor growth inhibition than [¹⁷⁷Lu]Lu-DOTA-MGS5. These findings suggest that [¹¹¹In]In/[¹⁷⁷Lu]Lu-MGS5-DA is a promising radiotheranostic pair for the treatment of CCK2R-expressing cancers.